Vascular Endothelial Growth Factor, a Possible Paracrine Growth Factor in Human Acute Myeloid Leukemia

Abstract

Vascular endothelial growth factor (VEGF ) is a multifunctional cytokine involved in angiogenesis, inflammation, and wound healing. It is secreted by a variety of tumor cell lines, including hematopoietic lines. Therefore, we investigated expression of VEGF and its receptors on fresh leukemic blasts. VEGF-specific transcripts were detected by polymerase chain reaction (PCR) in 20 of 28 patients with de novo acute myeloid leukemia (AML) and in 3 of 5 patients with secondary AML. Using immunocytochemistry, we found VEGF protein in 2 leukemic cell lines and in 8 AML patients, in concordance with PCR results. Supernatants of fresh leukemic cells from 24 AML patients contained significantly more VEGF than supernatants from bone marrow cells of 9 normal donors or of CD34-enriched cells from 3 normal volunteer donors as determined by an enzyme-linked immunosorbent assay. VEGF possesses two high-affinity receptors, KDR and FLT1. Using a sensitive nested PCR assay, we detected expression of FLT1 in 10 of 20 patients with de novo AML and 3 of 5 patients with secondary AML. KDR was expressed in 4 of 22 patients with de novo AML and 1 of 4 with secondary AML. To study possible paracrine growth stimulation of AML blasts, endothelial cells from human umbilical cords were incubated with increasing concentrations of VEGF. A dose-dependent increase of granulocyte-macrophage colony-stimulating factor secretion from endothelial cells was identified.

Clinical relevance of vascular endothelial growth factor receptors 1 and 2 in acute myeloid leukaemia and myelodysplastic syndrome

“…Accordingly, conditioned medium from VEGF-producing leukaemic cell lines was found to stimulate proliferation and/or chemotaxis in cultured endothelial cells (Vacca et al, 1998). VEGF mRNA and protein were also expressed in freshly isolated blasts from most patients with AML, and supernatants of fresh leukaemic cells from patients with AML contained significantly more VEGF than supernatants from bone marrow cells of normal donors (Fiedler et al, 1997a). VEGF paracrine growth stimulation of AML blasts in vivo was suggested by its stimulation of human umbilical cord endothelial cell production of granulocyte-macrophage colony-stimulating factor, a known stimulator of AML blast proliferation (Fiedler et al, 1997a).…”

“…Bellamy et al (1999) reported moderate to strong expression of VEGFR-1 mRNA in five of 12 leukaemia cell lines, but no VEGFR-2 mRNA expression in any of the 12 lines. Similarly, when studying VEGFR expression in fresh leukaemic blasts from patients with AML, Fiedler et al (1997a) found VEGFR-1 mRNA in 50% of cases and VEGFR-2 mRNA in 20% of cases. Ratajczak et al (1998) found detectable levels of VEGFR-1 mRNA in all samples examined from 15 patients with chronic-phase chronic myeloid leukaemia (CML) and seven patients with AML.…”

“…In the great majority of solid tumours, VEGF mRNA was expressed mostly in tumour cells, while VEGFR-1 and VEGFR-2 mRNA was expressed mostly in tumour-associated endothelial cells, suggesting the existence of a paracrine system (Ferrara, 1999). The existence of a similar paracrine system in leukaemia has been proposed (Fiedler et al, 1997a), but examination of VEGFR expression in leukaemic cells revealed the possible existence of a functional autocrine system as well. mRNAs for both VEGFR-1 and VEGFR-2 have been detected in some, but not all, leukaemia cell lines (Katoh et al, 1998;Ratajczak et al, 1998;Bellamy et al, 1999).…”

Significance of angiogenin plasma concentrations in patients with acute myeloid leukaemia and advanced myelodysplastic syndrome

“…Vascular endothelial growth factor (VEGF) and its receptors are expressed in leukaemic cells from most patients with AML, and serum VEGF levels are significantly higher than those in normal controls (Fiedler et al, 1997). High cellular VEGF levels are also a negative prognostic factor in AML (Aguayo et al, 1999).…”

A morphometric study of bone marrow angiogenesis in hairy cell leukaemia with clinicopathological correlations

“…The close proximity of the islands of haematopoietic cells to the normal bone marrow vessels (Branemark, 1968) and the common origin of haematopoietic and vascular endothelial cells during embryonic development (Choi et al, 1998) attest to an intimate liaison, in both a physical and a conceptual sense, between the bone marrow haematopoietic function and its vascular bed (Branemark, 1968). The production of haematopoietic growth factors by endothelial cells (Fiedler et al, 1997;De Bont et al, 2001;Keyhani et al, 2001) is in harmony with this concept. Recently, interest in bone marrow vascularity has revived owing to the realization that leukaemic cells might depend upon vascular support just like normal haematopoietic cells and the cells of most solid tumours (Mangi & Newland, 2000;Keyhani et al, 2001;Ribatti et al, 2001).…”